Two novel cDNAs, IA-1 and IA-2, were isolated and characterized from a human insulinoma subtraction library (ISL-153). IA-1 cDNA clone has a 2838 bp sequence consisting of an open reading frame of 1530 nucleotides which translates into a protein of 510 amino acids. The IA-1 protein can be divided into two domains based upon the features of its amino acid sequence. The N-terminal domain of the deduced protein sequence (1-250 a.a.) has four classical pro-hormone dibasic conversion sites and an amidation signal sequence, Pro-Gly-Lys-Arg. The C-terminal domain (251-510 a.a.) contains five putative zinc-finger DNA-binding motifs of the Cys2-His2 DNA-binding protein class. Northern blot analysis revealed that IA-1 mRNA is expressed primarily in neuroendocrine tumors. The restricted tissue distribution and unique sequence motifs suggest that this novel cDNA clone may encode a protein associated with the transformation of neuroendocrine cells. IA-2 cDNA clone has a 2937 bp open reading frame. The predicted amino acid sequence of IA-2 revealed a 979 amino acid protein which is consistent with a signal peptide, an extracellular domain, a transmembrane region and an intracellular domain. The extracellular domain contains an unusual cysteins-rich region following the signal peptide. The intracellular cytoplasmic domain of IA-2 possesses highly conserved regions similar to the phosphatase (PTP) family. IA-2 may represent a new member of the receptor-type PTP family with a distinct extracellular domain.